Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis in Cutaneous T-Cell Lymphoma Cells and Enhance Their Sensitivity for TNF-Related Apoptosis-Inducing.

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Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis in Cutaneous T-Cell Lymphoma Cells and Enhance Their Sensitivity for TNF-Related Apoptosis-Inducing Ligand Frank K. Braun, Nadya Al-Yacoub, Michael Plötz, Markus Möbs, Wolfram Sterry, Jürgen Eberle Journal of Investigative Dermatology Volume 132, Issue 2, Pages 429-439 (February 2012) DOI: 10.1038/jid.2011.316 Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease cell proliferation and induce apoptosis in cutaneous T-cell lymphoma cells. (a–c) For determination of dose response, HH, MyLa, HuT-78, and SeAx were incubated for 40hours with increasing concentrations of acetylsalicylic acid (ASA) and sodium salicylate (NaS; 1–5mM), as well as diclofenac (DF; 5–120μgml−1). (g, h) For time kinetic analysis, cells were harvested at 16, 40, and 72hours of treatment. Here, ASA and NaS were used at concentrations of 5mM, and DF was used at 60μgml−1 for HH and 120μgml−1 for MyLa, HuT-78, and SeAx. (a, g) Cell proliferation was determined by WST-1 assay, and values are expressed as percentage of nontreated controls (C=100%). (b, h) Apoptosis was quantified according to propidium iodide staining. Mean values±SDs of at least six values are shown. (c) Cytotoxicity was determined by lactate dehydrogenase release assay, and relative values were calculated with respect to untreated controls (C=1). (d) Representative histograms of DF-treated cells as determined by flow cytometry are shown. Apoptotic sub-G1 (sG1) cells, G1 and G2 populations are indicated. (e) Quantification of G2 population is shown for NSAID-treated (16hours) MyLa cells. The result was highly similar for the three other cell lines (data not shown). (f) Cell numbers were determined using a CASY Cell Counter and presented for HH as percentage of nontreated controls (C=100%). The result was highly similar for MyLa (data not shown). *Indicates statistical significance. Journal of Investigative Dermatology 2012 132, 429-439DOI: (10.1038/jid.2011.316) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Activation of the caspase (Csp) signaling cascade by nonsteroidal anti-inflammatory drugs. (a) Processing of caspases and Bid (western blotting) is shown for HH and MyLa treated for 24hours with acetylsalicylic acid (ASA; 3, 5mM), sodium salicylate (NaS; 3, 5mM), or diclofenac (DF; 30, 60μgml−1). Nontreated cells served as controls (C). Equal loading was confirmed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. (b) HH and MyLa were pretreated for 1hour with Q-VD-Oph, followed by treatment with ASA (5mM), NaS (5mM), or DF (60μgml−1) for additional 24hours. As a control, cells were treated for 40hours with an agonistic anti-CD95 antibody (CH-11, 50ngml−1). Apoptosis was quantified by propidium iodide staining. Means±SDs of a representative experiment with triplicate values are shown. Another experiment revealed similar results. *Indicates statistical significance. Journal of Investigative Dermatology 2012 132, 429-439DOI: (10.1038/jid.2011.316) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Loss of Δψm and downregulation of c-FLIP. (a) Loss of Δψm in HH and MyLa treated with acetylsalicylic acid (ASA; 5mM), sodium salicylate (NaS; 5mM), or diclofenac (DF; 60μgml−1) was determined by tetramethylrhodamine methyl ester perchlorate (TMRM+) staining (means±SDs of at least six individual values). (b) Representative histograms of nonsteroidal anti-inflammatory drug (NSAID)-treated cells (gray) in overlays with nontreated controls (C; white). The bar indicates the populations with low Δψm. (c) Mitochondrial (Mito) and cytosolic (Cyto) fractions of MyLa treated with NSAIDs for 40hours (concentrations as in a) were investigated for cytochrome c (Cyto c) release and Bax translocation. Lane 1: cytosolic and mitochondrial controls. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proved equal loading of cytosolic extracts and voltage-dependent anion channel (VDAC) excluded contamination of cytosolic extracts with mitochondria. (d) Reactive oxygen species (ROS) levels, according to dichlorodihydrofluorescein diacetate staining, are shown in response to DF (60μgml−1; repeated twice). (e) Nuclear localization of NF-κB subunits (p65, p50, and p52) is shown by western blot analysis in HH and MyLa cells treated for 16hours with NSAIDs (ASA and NaS 5mM, DF 60μgml−1 for HH and 120μgml−1 for MyLa). Lamin expression and ponceau staining proved equal loading. (f) Relative DNA-binding capacity of p65 in nuclear extracts of HH cells treated for 16hours with NSAIDs is shown as fold change. (g) Apoptosis induction in HH and MyLa cells pretreated with BMS-345541 (3μM) for 3hours, followed by NSAID treatment for additional 40hours is shown. Apoptosis was quantified according to propidium iodide staining. Mean values±SDs of a representative experiment are given. (h) Expression of c-FLIP, Bax, Bcl-2, Mcl-1, XIAP, and survivin is shown by western blotting in cutaneous T-cell lymphoma cells treated for 24hours with ASA (3, 5mM), NaS (3, 5mM), and DF (30, 60μgml−1). Equal loading was confirmed by GAPDH and c-FLIP expression was quantified by densitometriy (fold change). The whole experiment was performed twice. Journal of Investigative Dermatology 2012 132, 429-439DOI: (10.1038/jid.2011.316) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Decreased nonsteroidal anti-inflammatory drug-induced apoptosis after c-FLIPL overexpression. (a) Two independent MyLa cultures stably transduced with c-FLIPL (FLIPL-1/-2) or mock retrovirus were incubated for 40hours with acetylsalicylic acid (ASA; 5mM), sodium salicylate (NaS; 5mM), and diclofenac (DF; 60μgml−1), or with CH-11 agonistic CD95 antibody (50ngml−1, 24hours). Apoptosis was determined by propidium iodide (PI) staining. Values were normalized with regard to nontreated control cells (C=1). Means±SDs of a representative experiment (one of two in triplicates) are shown. (b) Transduction efficiencies were monitored by green fluorescent protein (GFP; filled graphs) as compared with non-transduced controls (open graphs). (c) Overexpression of FLIPL in transduced MyLa cells was proven by western blot analysis as compared with mock- and non-transduced cells. (d) Spontaneous apoptosis (PI staining) of untreated cells in response to transduction with cFLIPRNAi lentivirus (FL) as compared with ScrambleRNAi lentivirus (Sc) and non-transduced controls (C). Means±SDs of two independent experiments, each performed in triplicates, are shown. *Indicates statistical significance. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Journal of Investigative Dermatology 2012 132, 429-439DOI: (10.1038/jid.2011.316) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Enhancement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by combination with diclofenac. (a) Cutaneous T-cell lymphoma (CTCL) cells were treated for 24hours with acetylsalicylic acid (ASA; 5mM), sodium salicylate (NaS; 5mM), and diclofenac (DF; 60μgml−1). Surface expression of TRAIL (filled graphs, upper panel) and TRAIL-R2/DR5 (filled graphs, lower panel) in HH are shown in overlay histograms as compared with isotype controls (open graphs). Two experiments yielded similar results. (b) CTCL cells were treated for 40hours with ASA (5mM), NaS (5mM), or DF (60μgml−1). TRAIL was added for the last 16hours, when indicated. Apoptosis was quantified by propidium iodide staining. Mean values±SDs of a representative experiment are shown (two independent in triplicates). (c) Diclofenac and TRAIL-treated HH and MyLa cells were investigated by western blot analysis for caspase activation and c-FLIP expression. Caspase (Csp) cleavage products are indicated as (). Equal loading was confirmed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The experiment was repeated once, yielding highly comparable results. *Indicates statistical significance. NSAID, nonsteroidal anti-inflammatory drugs. Journal of Investigative Dermatology 2012 132, 429-439DOI: (10.1038/jid.2011.316) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Nonsteroidal anti-inflammatory drugss induce apoptosis in tumor T cells of cutaneous T-cell lymphoma patients. Tumor T cells of Sézary syndrome (SzS) patients (Pat 1–4) and CD4(+) control T cells of healthy donors (HD, one is shown here) were treated for 40hours with acetylsalicylic acid (ASA; 5mM), sodium salicylate (NaS; 5mM), and diclofenac (DF; 60μgml−1). Apoptosis was quantified by propidium iodide staining (upper panel). Relative cytotoxicity was determined according to lactate dehydrogenase release. Values were normalized with respect to nontreated controls (C=1, lower panel). Mean values of triplicates±SDs are shown. Journal of Investigative Dermatology 2012 132, 429-439DOI: (10.1038/jid.2011.316) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions